Geographic Variation in Drug Safety: Potentially Unsafe Prescribing of Medications and Prescriber Responsiveness to Safety Alerts

BACKGROUND: Drug safety issues represent a major cause of morbidity and mortality. Alerting programs are intended to identify patients at potential risk for adverse drug reactions and may provide relevant information to prescribers to support their decision making about clinically appropriate risk reduction. Geographic differences in the incidence of drug safety issues and the responsiveness of prescribers to alerting systems have not been previously studied. OBJECTIVES: To measure geographic differences in the rates of alerting events for potential drug safety issues, communicated to prescribers by mail or fax, and the responsiveness of prescribers to such alerts. METHODS: All alerts generated by a commercially available drug safety alerting program were evaluated for calendar year 2008 and were classified geographically based on patient residence. Primary study measures were (a) number of alerting events per 1,000 members (i.e., covered beneficiaries of all ages whose plan sponsor was enrolled in the alerting program service), and (b) therapy change rate (defined as the percentage of alerts that were followed by therapy modification consistent with the clinical alert). RESULTS: The program-wide aggregate rate of alerting events across all regions was 128 per 1,000 members, with the state-specific range from 78 to 240. The program-wide aggregate rate of drug therapy change across all regions was 54.0%, with the state-specific range from 48.1% to 59.5%. CONCLUSIONS: The rates of potential drug safety issues (alerting events) and the responsiveness of prescribers to drug safety alerts vary considerably by region and state. States with high issue rates and low therapy change rates may require additional prescriber outreach.

• Drug safety is a critical issue, with preventable adverse drug events contributing to significant unnecessary morbidity, mortality, and health care costs. As many as 28% of emergency room visits and 16.2% of hospital admissions are drug-related, with the majority being preventable. In a systematic review, Howard et al. (2006) found that a median of 3.7% (range 1.4% to 15.4%) of hospital admissions were attributable to preventable drug-related causes. • Medical decision making and medical care exhibit large regional variation, including hospitalization rates, procedures, and adherence to national guidelines. The magnitude of this variation is often by a factor of 3 to 5. However, geographic variation in the United States related to drug safety has not previously been described.

R E S E A R C H
• In an analysis of 1.6 million drug safety alerts generated by a large pharmacy benefits management company for 12.6 million eligible members of all ages in 2008, state-by-state safety alert rates ranged from 78 to 240 alerts per 1,000 eligible beneficiaries. • Variation was also seen in the regional rates of physician responsiveness to drug safety alerts, with success (therapy change) rates per alerting event ranging from 48.1% to 59.5% across states in the United States.

What this study adds
A ccording to the Institute of Medicine, "Pharmaceuticals are the most common medical intervention, and their potential for both help and harm is enormous." 1 More than 3.8 billion prescriptions are dispensed in the United States each year, costing over $291 billion. 2,3 These medications sometimes lead to significant unintended consequences, which are termed "adverse drug events" (ADEs). The Institute of Medicine estimates that over 1.5 million preventable ADEs occur in the United States each year. 4 As many as 28% of emergency room visits are drug related-of which 70% are preventable-with 24% resulting in hospital admission. 5 A systematic review and meta-analysis reported a median of 7.1% (interquartile range 5.7%-16.2%) of all hospital admissions resulted from ADEs, of which 59% were considered preventable. 6 Howard et al. (2006) found in a systematic review of 13 prospective observational studies that the median percentage of admissions due to preventable ADEs was 3.7% (range = 1.4% to 15.4%). 7 From an economic perspective, the cost of addressing ADE-related morbidity was over $177 billion in 2000, which exceeded the total cost of outpatient prescribed medication sales in that year. 8,9 Many factors contribute to these high rates of ADEs. Each year, prescribers are confronted with having to master the complexities of various new medications, as well as new data on the safe and effective use of thousands of existing drugs. Furthermore, patients increasingly require multiple medications to treat various conditions and comorbidities, increasing the potential for drug interactions, drug-disease conflicts, and ADEs. 10 Relying on physicians and other prescribers to maintain mastery of this increasingly complex situation from memory alone is an inadequate strategy. Furthermore, prescribers often do not have access to relevant patient information, including key diagnoses, because of inadequate coordination of care across multiple health care providers and inadequate integration of medical and pharmacy data. 11,12 Automated alerting systems have been developed to help mitigate this problem, using patient-specific data that have been integrated from a variety of medical and pharmacy sources. One such alerting system is provided by a pharmacy benefits management company (PBM), Medco Health Solutions, Inc., under the name RationalMed. This program includes thousands of algorithms that continuously analyze patient-level data to identify potential drug safety issues. When a potential problem is identified, such as a drug that is contraindicated when a patient has a particular disease as indicated by that patient's claims record, prescribers are alerted to the issue by mail or fax and provided with the relevant scientific evidence and patient-level data. One example of this intervention is the prescribing of medications for attention deficit hyperactivity disorder (ADHD) to a child with comorbid structural heart disease. The alert for this situation would describe the potential interaction, cite the relevant external sources including citations from the medical literature, and provide a summary of the patient's medical and pharmacy claims record, including contact information for other prescribers and pharmacies involved in the prescribing conflict.
In these alerting situations, the ultimate decision maker remains the physician or other prescribing health care professional. The alert itself has no role in any determination of drug coverage or copayment and is purely for the informational use of the prescriber. The role of the alerting system is to provide a complete view of the patient, as well as up-to-date literature-based recommendations, to facilitate improved decision making.
By virtue of having national reach, the largest drug safety alerting systems also provide an opportunity to undertake a geographic comparison of regions and states, exploring differences in prescribing and responsiveness to care-improvement alerts. Geographic variations in many elements of medical care have previously been reported, including the likelihood of hospitalization, procedure rates, prescribing of medications, and adherence with national care-improvement guidelines. [13][14][15][16][17][18] For example, the proportion of children with persistent asthma receiving influenza vaccination has been observed to vary regionally by a factor of 2, from 12.1% to 23.8%. 15 In contrast to the above examples, variations related to drug safety have not been sufficiently studied. This analysis describes the findings of a large-scale alerting program and explores geographic variation to help guide future prescriber outreach and support efforts.

■■ Methods
RationalMed, the source of the drug safety alerts evaluated in the present study, integrates outpatient pharmacy and medical claims data to identify potential drug safety issues. RationalMed also alerts on other issues, such as coordination of care (e.g., polypharmacy in seniors) and omission of essential care (e.g., omission of guideline-based drug therapy such as inhaled corticosteroids for severe asthma), although the focus of the present analysis was specifically on the subset of alerts pertaining to potential ADEs. The algorithms are developed and maintained by a team of physicians and pharmacists that has responsibility for ongoing surveillance to identify new clinical issues warranting incorporation into the program and necessary changes to existing algorithms and messages. Active surveillance is focused on FDA alerts, manufacturer alerts, product labeling changes, major national guidelines, and the peer-reviewed medical literature. The algorithms and messages are all based directly and entirely on those external sources, with explicit citations provided to prescribers who receive the alerts. Pharmacists then test each of these algorithms by performing detailed reviews of a sufficiently powered sample of individual patient profiles to assess the targeting accuracy based on their professional judgment in the context of the entire medical and pharmacy claims record.
The evaluation period for this analysis was calendar year 2008. During this time, roughly 12.6 million members throughout the United States were enrolled in the alerting program. Pharmacy claims were available for all members, since the study PBM directly provided their pharmacy benefits. Medical claims were provided to the PBM by all participating plan sponsors on a frequent basis, typically monthly, and were integrated with pharmacy claims. Pharmacy claims were present in 2008 for 60.3% of eligible members, and medical claims were present for 62.9% of eligible members.
All alerting events pertaining to potential ADEs for these 12.6 million members were included in the analysis. An alerting event was defined as a potential drug safety issue that generated an alert to 1 or more prescribers. The event count excludes the very small fraction of possible safety issues (1.47%) that could not be communicated to the prescribers for administrative reasons, such as invalid contact data. These alerting events were classified based on each patient's residence according to U.S. Census regions, divisions, and states.
Two key measures were evaluated for each geographic area. The first, the number of alerting events for potential safety issues identified per 1,000 members, is the prevalence rate of potentially unsafe prescribing situations. By dividing the observed number of alerting events by the number of members whose plan sponsors were enrolled in the program (which varies from region to region), the reported alerting event rate was adjusted for differences in population size as well as differences in the percent of the region's population enrolled in the alerting program. In calculating this rate, multiple discrete issues and alerting events for the same member were counted separately. Members who were potentially candidates for an alert, should their clinical situation warrant, included people of all ages regardless of any prior drug utilization.
The rates of safety alerting events were reported without Central nervous system stimulant is discontinued.

Adverse drug interaction
Drug prescribed conflicts with another drug that the patient is taking.
Discontinuation of either of the conflict medications or (when clinically applicable) reduction of either of the conflict medications to a safer dose

Risk of serious cardiac arrhythmias
Cases of QT prolongation with or without torsades de pointes have been reported in patients taking amiodarone concomitantly with azole antifungals. The decision to administer amiodarone with other drugs that prolong the QTc interval must be based on careful assessment of the potential risks and benefits for each patient.

Dose duration issue
Drug is prescribed at high dose for a longer duration than is usually recommended.
Discontinuation of the conflict medication, reduction to a safer dose, or (when clinically applicable) addition of a protective agent NSAID dose is lowered (or proton pump inhibitor is added).

Drug-age conflict
Drug is prescribed for use at an age above or below safe recommendations. Topical calcineurin inhibitor is discontinued.

Drug-pregnancy consideration
Drug prescribed during pregnancy is potentially unsafe to the fetus.

Risk of congenital malformations
Oligohydramnios, limb contractures, hypoplastic lung development, and renal failure have been reported with angiotensin-converting enzyme inhibitor use during the second and third trimester. First trimester exposure may be associated with defects of the cardiac septum, central nervous system, and urologic system. Discontinue the angiotensin-converting enzyme inhibitor as soon as possible in pregnant women.

Drug therapy duplication
Drugs prescribed share the same or similar mechanism of action. Atenolol is discontinued or metoprolol is discontinued. adjustment for any regional differences in age or disease burden because the intent of this analysis was to be fully descriptive of the extent of the potential safety issues identified and of regional differences attributable to all causes, including demographics as well as prescribing practice patterns.

Concomitant use of atenolol and metoprolol
The second key measure, success per alerting event, is the frequency of therapy changes that were consistent with the safety alert sent to the prescriber. In the example of a drug contraindicated in the context of a patient's disease, a success would be a change to a safer medication (i.e., without the contraindication), or drug discontinuation. Similarly, the success of alerts on dose-related issues would be defined by a change in the patient's prescription to a safer dose (calculated as strength times quantity divided by days supply). Changes in therapy were determined through systematic monitoring of each patient's prescription claims record during a specific window of time after each alert was sent to the prescriber. A success was recorded for the alert if, during that particular window, (a) neither the offending medication nor other medications with the same clinical concern were filled, or (b) the medication was not filled at an unsafe dose for dose-related alerts. For most prescriptions, that window begins on the earliest date that refills can be processed under most plans (when 75% of the alerted-upon medication would be used), and extends for 52 days thereafter. The window for 30-day fills begins on day 23 (75% of 30) and extends 52 days from then, ending on day 75. The window for 90-day fills begins on day 68 (75% of 90) and extends 52 days from then, ending on day 120. For pre-scriptions where the earliest next refill date is less than 15 days from the alert being generated, the start date of the measurement window is fixed at day 15 after the alerting event to ensure that the prescriber had likely received the alert prior to counting any change as an alerting success.
The types of drug safety issues and alerts that were included in this analysis are described in Table 1, with specific illustrative clinical examples from among the thousands of program algorithms, as well as the associated therapy changes that would define a success according to the methodology above.
Approval or exemption from an institutional review board (IRB) was not sought for this study. The analyses were conducted entirely from claims related to the pharmacy programs that the PBM routinely delivers on behalf of its clients. This manuscript does not include any individually identifiable health information. The authors and the PBM are authorized to use protected health information (PHI) in administering the RationalMed program under the "treatment, payment, and health care operations" provision of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 36 The authors and the PBM are bound to the covered entity by privacy and security standards that protect PHI, including HIPAA-compliant procedures for storage, transmission, release, and disposal of PHI. Table 2 describes by state the eligible population and the alerting events for potential safety issues identified in 2008. These Drug is prescribed for a duration that exceeds safe recommendations.

Risk of decreased bone density
Long-term use of depot medroxyprogesterone may cause a significant decrease in bone density during the initial years of treatment. Recovery of bone mass after drug discontinuation may be prolonged and incomplete.

Overview of Members Eligible for Alerting and Safety Issues Identified in 2008
alerting events were the basis for the success analysis. Table 2 also reveals the variation in the average number of distinct drug classes per member, using the Specific Therapeutic Class framework provided by First DataBank (San Bruno, CA). 37 Table 3 provides the rates of alerting events and the mean age for the program-eligible population in each of the U.S. Census regions and divisions. These data reveal that 13.2% of division-level variation in alerting events is explained by eligible member age. Figures 1 and 2 show each geographic region plotted on a 2-by-2 chart. The x-axis reflects the prevalence of potential safety issues (alerting events) per 1,000 members. The y-axis reflects success per alerting event, which is the rate of therapy change in response to the alert. Each chart also includes dotted lines to indicate the program-wide aggregate rates across all members in all regions and states. The aggregate rate of potential safety issues (alerting events) was 128 per 1,000 members. The aggregate rate of success per alerting event was 54.0%.
The full extent of the regional variation is demonstrated by the state-level data in Figure 2. Potential safety issues per 1,000 members ranged from the lowest rate in Alaska (78) to the highest rates in Washington, DC (240), followed by Louisiana, Michigan, and Alabama (180-182). Success per alerting event ranged from the lowest in North Dakota (48.1%) to the highest in Ohio (59.5%). Figure 2 graphically displays which quadrant each state falls into, based upon whether it is above or below the program-wide rates for each of the measured variables. These quadrant assignments are also depicted in a map of the United States in Figure  3, which shows the proximity of states with similar measured characteristics.

■■ Discussion
Geographic variation in medical decision making and patient management has been widely reported. 13 Prior research has extended from the utilization rates of certain procedures, such as back surgeries, to the likelihood of being prescribed narcotics or stimulant medications. [16][17][18]38 Studies also have measured geographic differences in clinical quality, largely defined as physician adherence to national guidelines for conditions such as asthma and heart disease, 14,15 and differences in the rates of preventive health services. 39 In contrast, little previous attention has been given to geographic variation related to drug safety issues. This study reveals considerable variation. The data in figures 1 and 2 can be interpreted best by quadrant, based on the divisions provided by the program-wide (weighted average) values for each measure. The "High Potential Safety Issues (Alerting Events), Low Success" quadrant is perhaps the most concerning, since the extent of the potential patient safety problem is the greatest, and the prescribers appear to be relatively resistant to addressing care improvement opportunities. The "Low Potential Safety Issues (Alerting Events), High Success" quadrant is the most reassuring. In these regions, fewer safety issues are identified, and of those that do arise, prescribers are more responsive to alerts to address them. The "High Potential Safety Issues (Alerting Events), High Success" quadrant may reflect a greater degree of provider reliance on alerting programs. In the "Low Potential Safety Issues (Alerting Events), Low Success" region, fewer events suggest fewer potential drug safety improvement opportunities, although prescribers are less responsive to alerts on the safety issues that do arise. One possible explanation could be that the most straightforward clinical situations are addressed by prescribers up-front, with the alertedupon issues representing more complex patient cases that reflect medical management challenges.
The map-based representation of these quadrants by state ( Figure 3) reveals that many states in close proximity tend to demonstrate similar patterns, suggesting that the variation may be related to pervasive regional factors such as prescribing practice patterns, disease prevalence, and demographics.
One of the contributors to the varying rates of potential safety issues is the underlying variation in rates of prescribing, which has previously been reported for several classes of medications. [16][17][18] The underlying reasons for these differences in prescribing rates have also been explored and fall into 4 major categories: physician characteristics, patient characteristics, regulations, and clinical management programs. Physician characteristics include specialty training, practice habits, and association with medical leaders who are "enthusiasts" about certain practice patterns. [16][17][18] Geographic Variation in Drug Safety: Potentially Unsafe Prescribing of Medications and Prescriber Responsiveness to Safety Alerts at the physician and patient level, is an opportunity for further research so that interventions can be deployed accordingly.
The Institute of Medicine has called for sweeping changes in health care processes to reduce ADEs. Among these recommendations is the expanded use of integrated data and coordination of care among physicians, using information technology and alerting systems such as the one described by this study. 4 Focused efforts to adopt these recommendations should use geographic and local data, such as those reported here, to target program enhancements and physician outreach.

Limitations
First, the safety alerting program described in this study treated all alerts equally regardless of potential seriousness, without differentiating among various drugs and safety concerns. Therefore, possible explanations for our findings include underlying Patient characteristics include age, gender, social environment, income, and race. 16,18 Regulations include state-specific monitoring programs. 17 Clinical management programs include those that help guide prescribers in their prescribing decisions and that sometimes influence the patient's medication coverage. 17,18 The relative contributions of differences in prescribing rates and other factors to the frequency of safety issues have not been well studied. Researchers in Scotland, Clark et al. (2007), provided insight into this question in association with the reporting of suspected adverse drug reactions (ADRs) to the National Health Service. 40 They concluded that approximately 44% of the variation in reports of certain ADRs can be explained by variations in prescribing rates after controlling for differences in regional population size. Therefore, roughly 56% of the ADR variation was unexplained by population size and prescribing rates and was attributable to other factors. Investigation of these other causes, differences in clinical issues or in the populations in the various regions. Second, we did not age-and gender-adjust our estimates. Tables 2 and 3 do show variation in average age, which can be viewed as a proxy for overall illness burden, although age variation does not explain 100% of the observed rate of drug safety issues. Table 1 also shows variation in the number of drug classes utilized per member, as another marker for overall disease burden. Because both patient factors and prescriber factors affect the rates of safety alerts, the findings of the present study should not be viewed as a simple reflection of the quality of individual prescribing decisions. However, the differences in rates are still meaningful because they may quantify differences in the opportunity for programmatic intervention. Third, prescribers could have received the same alert for the same patient on multiple occasions. The effect of this limitation on our success rate is unknown. Fourth, 100% success may not be a reasonable or clinically appropriate target for many alerts. In real-world medical care, patient-specific circumstances and exceptions may arise that warrant careful oversight without therapy modification. Furthermore, some data elements in medical or pharmacy claims may have been erroneously coded and processed. Therefore, the interpretation of success rates in this study should focus on the regional variation and not on the absolute values. Sixth, because market penetration for the program may vary by state, the degree to which our results represent actual statewide differences, as opposed to differences unique to members of our program, is unknown.

■■ Conclusions
Potential safety issues associated with prescription medications are common. Geographic variation exists in the rates of alerting events for such issues and in the success rates of alerts aimed at helping Potential Safety Issues and Prescriber Responsiveness to Alerts by State a A member is an enrolled person of any age whose plan sponsor uses the safety alerting program, regardless of whether the member filled any prescriptions during 2008.
prescribers reduce the risk of ADEs for their patients. Opportunity exists to collaborate with local and regional medical organizations, in addition to those who pay for the high costs of medical care associated with ADEs, to help improve both measures.